Project V (Mucus Dehydration and Evolution of COPD Lung Disease; R. Boucher, P.I.) will test the[unreadable] hypothesis that a significant component of the chronic bronchitic phenotype of COPD reflects the relative[unreadable] dehydration of airway mucus (secretions), which produces mucus adhesion to airway surfaces, infection of[unreadable] mucus with bacterial communities, inflammation, and airflow obstruction. Sp. Aim 1 will test this hypothesis[unreadable] directly in cross-sectional cohorts of Gold 0/1,2, and 3 subjects, measuring: 1) COPD mucociliary (MCC)[unreadable] and cough clearance (CC); 2) mucus hydration (water content/activity); 3) the concentrations of the dominant[unreadable] regulators of airway hydration, i.e., purine nucleotides (ATP) and nucleosides (ADO); and 4) the[unreadable] consequences of mucus dehydration on mucus biophysical properties and bacterial infection. Sp. Aim 2[unreadable] tests the hypotheses that: 1) COPD acute exacerbations (AEs) reflect a transient worsening/failure of the[unreadable] mucus clearance (ciliary/cough-dependent) mechanism; 2) the COPD patient is vulnerable to triggers of AEs[unreadable] because mucus clearance is chronically compromised by cigarette smoke-induced mucus dehydration; and[unreadable] 3) respiratory viruses trigger many COPD AEs via direct infection of the lower airway epithelium and[unreadable] derangement of the extracellular ATP/adenosine and cytokine pathways that regulate salt/water transport[unreadable] and mucin secretion rates. Finally, we hypothesize that we can do little to acutely downregulate mucin[unreadable] secretion during an AE. In Sp. Aim 3, we test whether we can rehydrate the abnormal (dehydrated) mucus[unreadable] that we speculate is characteristic of an AE via inhalation of hypertonic saline (HS), and whether it is safe to[unreadable] deliver HS to a COPD patient with an AE. Thus, we will test this hypothesis by exposing COPD subjects[unreadable] before (to assess safety) and during an AE to inhaled 7% HS and test acute (surrogate) efficacy via[unreadable] measures of mucus clearance and spirometry. This project depends heavily on Project IV (D. Peden) and[unreadable] Project VI (S. Donaldson) for comparative normal and CF data describing mucus composition (hydration,[unreadable] nucleotides+nucleosides, and mucin molecules). The ultimate goals articulated in this Project for the U.S.[unreadable] COPD patient population are to generate a mechanistic understanding of the failure in host defense that[unreadable] produces COPD and test novel approaches to restore host defense aimed at rehydrating the surface of the[unreadable] COPD lung.